3015 - Hierarchically Related Lineage-Restricted Fates of Multipotent Hematopoietic Stem Cells

Abstract

Self-renewing bone marrow hematopoietic stem cells (HSCs) secure blood cell replenishment in homeostasis and upon stress stimuli. Single cell transplantations uncovered considerable heterogeneity among HSCs (Müller-Sieburg et al. Blood 2002; Dykstra et al. Cell Stem Cell 2007; Challen et al. Cell Stem Cell 2010), also supported by findings in unperturbed hematopoiesis (Busch et al. Nature 2015; Pei et al. Nature 2017; Rodriguez-Fraticelli et al. Nature 2018). Expression of the megakaryocytic (Mk) von Willebrand factor gene (Vwf) enriches for platelet-biased HSCs (Sanjuan-Pla et al. Nature 2013). Some studies also suggested direct generation of unipotent self-renewing Mk progenitors within the phenotypic HSC compartment, implicating uncoupling between self-renewal and multipotency (Yamamoto et al. Cell 2013; Haas et al. Cell Stem Cell 2015). In this study (Carrelha et al. Nature 2018), sensitive tracking of progenitors and mature cells of the Mk/platelet (P), erythroid (E), myeloid (M), B and T cell lineages upon single HSC transplantation revealed a stable hierarchical framework for lineage-restricted fates of HSCs. The Vwf- HSC compartment includes long-term (LT) and short-term (ST) multilineage HSCs, with lymphoid-biased output resulting from ST-HSC exhaustion. In addition to multilineage HSCs, the Vwf+ compartment includes distinct subsets adopting PEMB-restricted, PEM-restricted, PE-restricted and P-restricted fates. Sustained self-renewal potential and unfulfilled multipotency of these fate-restricted HSCs is revealed through serial transplantation and in vitro assays, respectively. The only unilineage-fate subset of serially-transplantable HSCs replenish exclusively the Mk lineage branch of the hematopoietic tree, and no LT-HSC subset was found contributing exclusively to another single lineage. Genetic lineage tracing with Vwf-Cre inducible mouse model also supports an important role for platelet-biased HSCs in unperturbed hematopoiesis. Our findings uncover a limited repertoire of LT-HSC subsets, defined by hierarchically organised propensities for replenishment of a restricted set of blood lineages, prior to loss of self-renewal and multipotency.